Musculoskeletal Pain among Breast Cancer Survivors: Through Bio-behavioral and Imaging Lenses Musculoskeletal pain (MP) is a leading cause of physical disability and can be triggered or exacerbated by systemic cancer treatments, such as chemotherapy (e.g., taxane-based), endocrine therapy (aromatase inhibitors [AIs]), and immunotherapy (checkpoint inhibitors). MP is particularly common among women taking AI therapy, which is generally prescribed for 5-10 years for postmenopausal women with hormone-sensitive breast cancer. MP (including arthralgias, myalgia, and joint/muscle stiffness) is experienced by up to 85% of AI users, and is the number one contributor to the high treatment discontinuation rate (up to 73%). While strategies have been proposed to manage MP with AI therapy, there are still no consistently effective interventions to prevent or manage the problem, due in large part because the phenotype of MP has not been well-characterized and the mechanisms underlying MP have not been clearly explicated. Aiming to better characterize the phenotype of MP and gain a greater understanding of mechanism underlying MP, we propose a line of studies. The central hypothesis of these studies is that the influences of AI therapy on the phenotype of MP and MP-related alterations in deep tissues and the central nervous system are moderated by multiple genetic variabilities. The dissertation project (F99 study) will investigate the inter-individual variability of long- term trajectories (18 months) of MP with AI for breast cancer using a biobehavioral framework. The inter- individual variability of MP, and its related phenotypic and contextual factors will be examined. The association between inter-individual variability of MP and genotypic factors (DNA variation in genes related to estrogen biosynthesis, AI metabolism, inflammation, and musculoskeletal disorders) will be explored. In the postdoctoral project (K00 study), imaging techniques will be incorporated as a brand-new lens to describe the phenotype of MP and its related alterations in deep tissues (joints and muscles) and the central nervous system (the brain). The relationship among self-reported MP, structural joints/muscles pathology, and structural and functional alterations in the brain will be first described and explored among breast cancer survivors. The proposed F99/K00 training and studies are aimed at establishing a unique model integrating omics, imaging and behavioral data to provide greater insight into the phenotype and mechanisms of MP, and serve as the basis for predicting MP with AI therapy and development of individualized interventions.